CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Dorothy M. Adcock, MD
July 2018—With the introduction of direct oral anticoagulants (DOAC) there is a paradigm shift in the use and understanding of screening coagulation tests to determine a patient’s bleeding risk. In patients on DOAC therapy, clinicians cannot rely on normal activated partial thromboplastin time (APTT) and prothrombin time (PT) results to reflect the patient’s level of anticoagulation. Historically, these tests have been used to determine whether it is safe to allow emergency treatment, such as the use of thrombolytic therapy or the performance of an invasive procedure, in anticoagulant-treated patients. DOAC-treated patients, however, can be therapeutically anticoagulated yet have normal APTT and PT results. Laboratory scientists should actively engage in educational activities and provide consultation to bring this potential patient safety issue to the attention of our clinical colleagues.
Since initial Food and Drug Administration approval in 2010, DOAC use for the treatment of conditions that require long-term anticoagulation (for example, atrial fibrillation, pulmonary embolism) has been increasing. Advantages over oral vitamin K antagonists such as warfarin are substantial, including a lower incidence of intracranial bleeding, no dietary restrictions, and fixed-dose administration, without the need for routine (episodic) laboratory monitoring. Indeed, in 2016 the American College of Chest Physicians recommended the use of DOACs over vitamin K antagonists for the treatment of non-cancer-related venous thrombosis.
In general, there is a poor correlation between plasma concentrations of DOACs and prolongation of the APTT and PT. Drug effect on clotting time depends considerably on the specific DOAC administered and the particular APTT and/or PT reagent used. Early guidelines on DOAC therapy suggested that normal APTT and PT results would indicate that DOAC concentrations were sufficiently low to allow emergency treatment. The major shortcoming of these early recommendations is that they were primarily based on the use of contrived samples (DOAC-spiked normal plasma) or the use of commercial calibrators to assess APTT and PT reagent responsiveness (sensitivity).
Dr. Adcock
Contrived DOAC samples do not demonstrate the same correlation with DOAC concentrations as samples from patients on DOAC therapy and cannot be used to accurately predict reagent responsiveness to DOACs. Similarly, the use of DOAC calibrators to determine reagent responsiveness may significantly overestimate APTT and PT responsiveness to DOACs and thus provide an unrealistic and unsafe assumption that normal screening tests suggest the absence of therapeutic levels of DOACs. Data from more recent publications have assuredly refuted both of these early recommendations and have substantiated that normal APTT and PT results, even when using DOAC-responsive reagents, are not able to safely identify DOAC concentrations below the suggested safe-for-treatment threshold (30–50 ng/mL), especially in apixaban-treated patients. Of note, the most recently approved DOAC, betrixaban, has very little published information about the response of coagulation screening tests.
Laboratories should consider alternative strategies for assessing DOAC presence using methods that provide higher sensitivity and safe lower limits of detection. The thrombin time is highly sensitive to dabigatran, and a normal thrombin time virtually excludes dabigatran presence. The chromogenic anti-Xa method used for heparin testing can be calibrated with the specific DOAC to be measured in order to determine a quantitative drug level or can be used as a screening test to exclude the presence of anti-Xa DOACs.